T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex.
T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex.
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T-bet通过介体和超伸长络合物激活Th1基因。
DOI：
10.1016/j.celrep.2016.05.054
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发表时间：
2016-06-21
期刊：
影响因子：
8.8
通讯作者：
Jenner RG
中科院分区：
文献类型：
--
作者：
Hertweck A;Evans CM;Eskandarpour M;Lau JC;Oleinika K;Jackson I;Kelly A;Ambrose J;Adamson P;Cousins DJ;Lavender P;Calder VL;Lord GM;Jenner RG
转录因子T-bet指导Th 1细胞分化，但这种谱系特异性基因调控的分子机制尚不完全清楚。在这里，我们表明T-bet通过增强子起作用，以允许以超延伸复合物（SEC）的形式募集介体和P-TEFb。Th 1基因在Th 2细胞中被H3 K4 me 3和RNA聚合酶II占据，而T-bet介导的P-TEFb在Th 1细胞中的募集激活转录延伸。P-TEFb被募集到基因和增强子中，在那里它激活增强子RNA转录。P-TEFb抑制和Mediator和SEC敲低选择性阻断T-bet靶基因的激活，P-TEFb抑制消除了Th 1相关的实验性自身免疫性葡萄膜炎。T-bet活性与NF-κB B RelA和Brd 4结合的变化无关，T-bet和NF-κ B介导的途径相反会聚以允许P-TEF B募集。这些数据提供了深入了解谱系特异性因子促进替代T细胞命运分化的机制。Th 1基因和Th 2基因与RNA pol II在替代谱系中相关T-bet作用于募集Mediator和SEC以激活Th 1基因和eRNA T-bet和NF-κ B依赖性P-TEFb募集途径在增强子处会聚P-TEFb抑制沉默T-bet靶基因并废除葡萄膜炎体内谱系特异性转录因子控制T辅助细胞命运选择，但其潜在机制尚不清楚。Hertweck等人揭示了Th 1基因在替代性Th 2谱系中经历转录起始，并且Th 1主调节因子T-bet的功能是募集介体和超延伸复合物以激活转录延伸。
The transcription factor T-bet directs Th1 cell differentiation, but the molecular mechanisms that underlie this lineage-specific gene regulation are not completely understood. Here, we show that T-bet acts through enhancers to allow the recruitment of Mediator and P-TEFb in the form of the super elongation complex (SEC). Th1 genes are occupied by H3K4me3 and RNA polymerase II in Th2 cells, while T-bet-mediated recruitment of P-TEFb in Th1 cells activates transcriptional elongation. P-TEFb is recruited to both genes and enhancers, where it activates enhancer RNA transcription. P-TEFb inhibition and Mediator and SEC knockdown selectively block activation of T-bet target genes, and P-TEFb inhibition abrogates Th1-associated experimental autoimmune uveitis. T-bet activity is independent of changes in NF-κB RelA and Brd4 binding, with T-bet- and NF-κB-mediated pathways instead converging to allow P-TEFb recruitment. These data provide insight into the mechanism through which lineage-specifying factors promote differentiation of alternative T cell fates. Th1 genes and Th2 genes are associated with RNA pol II in the alternative lineage T-bet acts to recruit Mediator and the SEC to activate Th1 genes and eRNAs T-bet and NF-κB-dependent P-TEFb recruitment pathways converge at enhancers P-TEFb inhibition silences T-bet target genes and abrogates uveitis in vivo Lineage-specifying transcription factors control T helper cell fate choice, but the mechanisms underlying this are unclear. Hertweck et al. reveal that Th1 genes undergo transcriptional initiation in the alternative Th2 lineage and that the Th1 master regulator T-bet functions to recruit Mediator and the super-elongation complex to activate transcriptional elongation.